This proposal includes seven components aimed to define the genetic and toxic causes of mental retardation, and the interrelationships which exist between them. Included are a study of mucolipidosis II (I-cell disease) and mucolipidosis III, a genetically determined disorder of glycosaminoglycan and glycolipid metabolism, with emphasis on a sialidase deficiency, which was first described in this laboratory. A second component focuses on genetically determined disorders of cholesterol ester or fatty acid metabolism in adrenoleukodystrophy and Refsum's disease. A third component is concerned with the regulation of proline metabolism, including studies of human hyperprolinemia, one of the aminoacidurias which may be associated with mental retardation. A fourth study attempts to determine if there are definable genetic factors in a disorder or group of disorders which manifest in the behavioral sphere, namely the reading disabilities. Studies on the toxic causes of mental retardation will extend present knowledge about lead toxicity, by examining also the roles of zinc, iron, cadmium, mercury, copper and manganese, by focusing on the roles and effects of these substances in the fetus and in young infants, and by studies of the effects of certain genetic disorders such as sickle cell disease and lactose intolerance on the susceptibility to the toxic effects of trace metals. A study on teratogens will examine the hypothesis that the formation of arene oxides represents a general mechanism for the teratogenic actions of substances such as dilantin and benzpyrene. Of particular interest here is an attempt to validate an in-vitro system for predicting teratogenic potential. This system would also facilitate the identification of genetic factors which may enhance of diminish the fetus' susceptibility to teratogens.